Apr 18 2006
According to Canadian and American researchers they have identified one reason why drugs like Celebrex and Vioxx - once popular for the treatment of pain and inflammation - cause heart problems.
Researchers at Queen's University and the University of Pennsylvania say their findings offer the prospect of a new generation of anti-inflammatory drugs that will bypass this issue.
Colin Funk, a professor of Biochemistry and Physiology at Queen's, and Canada Research Chair in Molecular, Cellular and Physiological Medicine and a co-author of the study, says although the results are in mice they raise an exciting possibility which can be tested in humans.
The link between selective inhibitors of COX-2 such as Vioxx, Bextra and Celebrex with an increased incidence of heart attack and stroke, has created interest in understanding the mechanism involved.
The researchers say that clarification of this issue will offer the prospect of conserving the clinical benefit of such drugs for patients with arthritis, while managing the risk.
The investigators first compared genetically manipulated mice that mimic the impact of either COX-2 inhibitors or low-dose aspirin with healthy mice treated with or without COX-2 inhibitors, such as Celebrex.
They say a small cardiovascular risk was seen with the COX-2 inhibitors but aspirin diminished the hazardous effects of the COX-2 inhibitors.
The investigators also found that not only the clotting response, but also the rise in blood pressure caused by drugs like Celebrex, was reduced.
The studies indicate that aspirin would limit the cardiovascular risk, but may increase the risk of stomach problems.
A more promising finding came from a drug target that might substitute for COX-2: an enzyme called microsomal prostaglandin E synthase (mPGES)-1.
The researchers showed that blocking this enzyme in mice did not predispose the animals to thrombosis or elevate blood pressure.
Co-author with Dr. Funk on the study was Dr. Garret FitzGerald, director of Penn's Institute for Translational Medicine and Therapeutics.
Funding comes from the U.S. National Institutes of Health and a grant from Merck.
The study is published in the on-line edition of the Journal of Clinical Investigation.